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WO2006111285A2 - Imino-oxazolidines et leur utilisation - Google Patents

Imino-oxazolidines et leur utilisation Download PDF

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Publication number
WO2006111285A2
WO2006111285A2 PCT/EP2006/003232 EP2006003232W WO2006111285A2 WO 2006111285 A2 WO2006111285 A2 WO 2006111285A2 EP 2006003232 W EP2006003232 W EP 2006003232W WO 2006111285 A2 WO2006111285 A2 WO 2006111285A2
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formula
hydrogen
amino
alkyl
compound
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PCT/EP2006/003232
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German (de)
English (en)
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WO2006111285A3 (fr
Inventor
Susanne Röhrig
Jens Pohlmann
Elisabeth Perzborn
Christoph Gerdes
Karl-Heinz Schlemmer
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Bayer Healthcare Ag
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Priority to AT06724168T priority Critical patent/ATE487714T1/de
Priority to EP06724168A priority patent/EP1874764B1/fr
Priority to DE502006008280T priority patent/DE502006008280D1/de
Priority to US11/919,020 priority patent/US20100048548A1/en
Priority to JP2008506966A priority patent/JP2008536883A/ja
Priority to CA002605492A priority patent/CA2605492A1/fr
Publication of WO2006111285A2 publication Critical patent/WO2006111285A2/fr
Publication of WO2006111285A3 publication Critical patent/WO2006111285A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present application relates to novel imino-oxazolidines, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular of thromboembolic diseases.
  • Blood clotting is a protective mechanism of the organism that can quickly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and bleeding after vascular injury is essentially through the coagulation system, which involves an enzymatic cascade It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, ending the cascade with the transformation of the soluble fibrinogen into the insoluble fibrin Traditionally, one distinguishes between the intrinsic and extrinsic systems in the blood coagulation, which culminate in a final common pathway, in which the factor Xa, which is formed by the proenzyme factor X, plays a key role, as both coagulation paths The activated serine protease Xa cleaves prothrombin to thrombin.
  • thrombin in turn splits fibrinogen to fibrin. Subsequent cross-linking of the fibrin morphiomers leads to the formation of blood clots and thus to haemostasis. In addition, thrombin is a potent trigger of platelet aggregation, which also makes a significant contribution to hemostasis.
  • Hemostasis is subject to a complex regulatory mechanism.
  • An uncontrolled activation of the coagulation system or a defective inhibition of the activation processes can cause the formation of local thromboses or embolisms in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thromboembolic diseases.
  • hypercoagulability - systemically - in case of consumption coagulopathy can lead to disseminated intravascular coagulation.
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • VTE venous thromboembolism
  • heparin is used, which is administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, low molecular weight heparin is increasingly preferred today; However, this also the known disadvantages described below can not be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. Since heparin simultaneously inhibits several factors of the blood coagulation cascade, there is an unselective effect.
  • a second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indandiones, but especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which are unsuitable for the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. Due to the mechanism of action, the effect is only very slow (latency until the onset 36 to 48 hours). Although the compounds can be administered orally, due to the high risk of bleeding and the narrow therapeutic index, a complex individual adjustment and observation of the patient is necessary [J. Hirsh, J. Dalen, D.R.
  • factor Xa is one of the most important targets for anticoagulant drugs [J. Hauptmann, J. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S., Thrombosis Research 1999, 93, 203; SAV Raghavan, M. Dikshit, "Recent Advances in the Status and Targets of Antithrombotic Agents" Drugs Fut. 2002, 27, 669-683; HA Wieland, V. Laux, D. Kozian, M.
  • the object of the present invention is to provide novel substances for controlling diseases, in particular thromboembolic diseases.
  • the present invention relates to compounds of the general formula (I)
  • A is a group of the formula
  • R 4 is hydrogen, (C r C6) alkyl, (C 3 -C 7) cycloalkyl, hydroxy, (C r C 6) alkoxy, amino, mono- or di- (Ci-C 6) alkylamino, (C 3 -C 7 ) -cycloalkylamino, (Ci-Cg) -alkanoyl-amino or (Ci-C 6 ) alkoxycarbonylamino, wherein
  • R 5 is hydrogen or (C r C 4) alkyl
  • R 6 and R 7 are identical or different and are independently (Ci-C ⁇ ) alkyl or (C 3 -C 7) -cycloalkyl
  • R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated or partially unsaturated heterocycle which is a
  • R 8 is hydrogen or (C r C 6) alkyl
  • Z is phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl or pyrrolyl, each one or two times, identically or differently, by substituents selected from the group consisting of halogen, cyano, (Ci-C 4 ) alkyl, which in turn by Hydroxy or amino may be substituted, ethynyl, cyclopropyl and amino may be substituted,
  • R 1 and R 2 are identical or different and independently hydrogen, halogen, cyano, (C r C4) alkyl, cyclopropyl, trifluoromethyl, hydroxy, (C r C4) alkoxy, methoxy trifluoro, amino, mono - or di- (Ci-C 4 ) -alkylamino, wherein
  • (C r C 4) -alkyl and (C r C 4) -alkoxy for their part in each case by hydroxy, (C r C 4) alkoxy, amino, mono- or di- (Ci-C 4) alkylamino or (C 3 -C 7 ) -cycloalkylamino may be substituted,
  • R 3 is hydrogen, (C r C 6 ) -alkyl or cyano
  • Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts encompassed by formula (I) and those of the formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore comprises the Enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • (C 1 -Q) -alkyl and (C 1 -C 4 -alkyl in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, preferably a straight-chain or branched alkyl radical having 1 to 4 carbon atoms
  • the following are preferably mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.
  • Q-cycloalkyl represents a monocyclic cycloalkyl group having from 3 to 7 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms is preferred, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • (C 1 -Q) -alkoxy and (C 1 -Q) -alkoxy are a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Q-QVAlkanoyl [(C r C6) acyl] is in the context of the invention a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries in the 1-position a doubly bonded oxygen atom and is attached via the 1-position
  • a straight-chain or branched alkanoyl radical having 1 to 4 carbon atoms may be mentioned by way of example and preferably: formyl, acetyl, propionyl, n-butyryl, isobutyryl and pivaloyl.
  • (Q-Q-alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms which is linked via a carbonyl group
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group is preferred called: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • Mono- (Q-Q) -alkylamino and mono- (Q-Q) -alkylamino in the context of the invention represent an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Di- (C 1 -C ⁇ ) alkylamino and di- (Ci -Q) -alkylamino in the context of the invention an amino group with two identical or different straight-chain or branched alkyl substituents each having 1 to 6 or 1 to 4 carbon atoms.
  • Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred.
  • N N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N -methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • fC r C7VCvcloalkylamino is in the context of the invention for an amino group having a cycloalkyl substituent having from 3 to 7 carbon atoms. Preference is given to a cycloalkylamino radical having 3 to 6 carbon atoms. Examples which may be mentioned are: cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino.
  • (C r C ⁇ VAlkanoylamino is in the context of the invention an amino group having a straight-chain or branched alkanoyl substituent which has 1 to 6 carbon atoms and is attached via the carbonyl group. Preference is an alkanoylamino radical containing 1 to 4 Examples which may be mentioned are: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
  • C 1 -C 4 -alkoxycarbonylamino is an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxy radical and is linked via the carbonyl group
  • the following may be mentioned by way of example and preferably: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and tert-butoxycarbonylamino.
  • a 4- to 7-membered heterocycle in the context of the invention is a saturated heterocycle having 4 to 7 ring atoms, which contains a ring nitrogen, is linked via this and can contain a further heteroatom from the series ⁇ or O as a ring member , Preference is given to a 5- or 6-membered saturated, ⁇ -linked heterocycle which may contain a further heteroatom from the series ⁇ or O.
  • Examples which may be mentioned are: azetidinyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl and 1,4-diazepinyl. Particularly preferred are pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • a 4- to 6-membered saturated or partially unsaturated Heterocvclus is in the context of the invention for a heterocycle having 4 to 6 ring atoms, which contains a ring nitrogen atom is linked via this, another heteroatom from the series ⁇ or O as a ring member may be and is saturated or contains a double bond.
  • Preference is given to a 5- or 6-membered saturated or partially unsaturated, ⁇ -linked heterocycle which may contain a further heteroatom from the series ⁇ or O.
  • Examples include: azetidinyl, pyrrolidinyl, oxa Zolidinyl, imidazolidinyl, pyrrolinyl, pyrazolinyl, Lnidazolinyl, 4-oxazolinyl, isoxazolinyl, piperidinyl, piperazinyl, Mo ⁇ holinyl, tetrahydropyridinyl and tetrahydropyrimidinyl. Particularly preferred are pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl and morpholinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine or chlorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • A is a group of the formula
  • R 4A is hydrogen, hydroxy, methoxy or amino
  • R 4B is methyl or ethyl, which may each be substituted by hydroxy, amino, pyrrolidino or cyclopropylamino, or amino,
  • R 4C is hydrogen, methyl or ethyl, where methyl and ethyl may each be substituted by hydroxy, amino, pyrrolidino or cyclopropylamino,
  • R 9 is fluorine, chlorine, methyl or ethynyl
  • R 1 is hydrogen
  • R 2 is hydrogen, fluorine or methyl
  • R 3 represents hydrogen or are (C r C4) alkyl
  • A is a group of the formula
  • Z is a group of the formula
  • R 9 is fluorine, chlorine or methyl
  • R 1 is hydrogen
  • R 2 is hydrogen, fluorine or methyl
  • R 3 is hydrogen
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention in which R 3 is hydrogen, which comprises (2iS) -3-aminopropane-1,2-diol of the formula (II)
  • X is a suitable leaving group, for example halogen, preferably chlorine,
  • R 3 cyano: a) R. Evers, M. Michalik, J. Prakt. Chem. 1991, 333, 699-710; N. Maezaki, A. Furusawa, S. Uchida, T. Tanaka, Tetrahedron 2001, 57, 9309-9316; G. Berecz, J. Reiter, G. Argay, A. Kalman, J. Heterocycl. Chem. 2002, 39, 319-326; b) R. Mohr, A. Buschauer, W.
  • the compounds according to the invention can also be prepared by further conversions of functional groups of individual substituents, in particular those listed under R 1 , R 2 , R 4 , R 6 and R 7 , starting from the compounds of the formula (I) obtained by the above process.
  • transformations are carried out by conventional methods and include, for example, reactions such as alkylation, amination, acylation, esterification, ester cleavage, amide formation, oxidation or reduction, and the introduction and removal of temporary protecting groups.
  • Inert solvents for process step (II) + (DT) -> • (IV) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers, such as diethyl ether, dioxane, tetrahydroethane.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, dioxane, tetrahydroethane.
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions
  • solvents such as acetone, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DM
  • (2S) -3-aminopropane-l, 2-diol (IT) can be used in this process step as a free base or as an acid addition salt;
  • the hydrochloride is used.
  • Suitable bases for process step (II) + (DT) - »(PV) are customary inorganic or organic bases. These include in particular alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or pyridine. Preference is given to using sodium bicarbonate.
  • alkali metal bicarbonates such as sodium or potassium bicarbonate
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or pyridine. Preference is given to using sodium bicarbonate.
  • the base is used here in an amount of 1 to 3 mol, preferably in an amount of 1 to 2 mol, based on 1 mol of the compound of formula (H) or its hydrochloride.
  • the reaction is generally carried out in a temperature range of 0 0 C to +50 0 C, preferably from + 5 ° C to +30 0 C.
  • reaction (IV) -> (V) is carried out with 1 to 5, preferably 3 to 5 equivalents of aqueous hydrobromic acid in acetic acid, optionally with the addition of acetic anhydride.
  • the reaction is generally carried out in a temperature range of +20 0 C to +100 0 C, preferably +50 0 C to +80 0 C.
  • Inert solvents for process step (V) -> (VI) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned.
  • Suitable bases for the cyclization (V) -> (VI) are customary inorganic bases. These include, in particular, alkali metal bicarbonates, such as sodium or potassium bicarbonate, or alkali metal or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonate. Preferably, potassium carbonate is used.
  • the base is used here in an amount of 1 to 5 mol, preferably in an amount of 3 to 5 mol, based on 1 mol of the compound of formula (V).
  • the reaction takes place in general my 5O 0 C in a temperature range of 0 0 C to +, preferably from +10 0 C to + 3O 0 C.
  • Inert solvents for process step (VI) + (VII) -> (VIII) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as acetone, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane, tetrahydrofuran, ethanol or mixtures thereof with water are preferably used.
  • the process step (VI) + (VIT) - »(VE!) can optionally also be carried out with the addition of a catalytic amount of a protic acid, such as p-toluenesulfonic acid, or a Lewis acid, such as ytterbium (III) trifluoromethanesulfonate ,
  • a protic acid such as p-toluenesulfonic acid
  • a Lewis acid such as ytterbium (III) trifluoromethanesulfonate
  • reaction of (VI) + (VD) -> (VIS) is generally carried out in a temperature range from 0 ° C to +100 0 C, preferably +20 0 C to + 8O 0 C.
  • Inert solvents for process step (VW) -> (IA) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane or 1,2-dichloroethane, ethers such as diethyl ether, dioxane or tetrahydrofuran, hydrocarbons such as benzene, xylene, toluene , Hexane, cyclohexane or petroleum fractions, or other solvents such as acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran or acetonitrile.
  • the process step (VIH) - »(I-A) can advantageously be carried out with the addition of a strong inorganic or organic acid.
  • a strong inorganic or organic acid include in particular acids such as fluorine-hydrogen, hydrogen chloride, hydrogen bromide, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid.
  • reaction (VIII) - »(IA) is generally carried out in a temperature range from -2O 0 C to + 50 ° C, preferably from 0 0 C to + 40 0 C.
  • All process steps can be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the compounds of the invention show an unpredictable, valuable pharmacological activity spectrum, in particular a high potency.
  • the compounds according to the invention are selective inhibitors of the blood coagulation factor Xa, which act in particular as anticoagulants.
  • the compounds of the invention have favorable physicochemical properties, such as good solubility in water and physiological media, which is advantageous for their therapeutic use.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of thromboembolic diseases and / or thromboembolic complications.
  • thromboembolic disorders include senns- special diseases such as -Herzinfarkt with ST-segment increase (STEMI) and without ST-
  • Segment elevation (non-STEMT), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis following coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive disease, pulmonary embolism, deep venous thrombosis and
  • Renal vein thrombosis Renal vein thrombosis, transient ischemic attacks and thrombotic and thromboembolic stroke.
  • the substances are therefore also useful in the prevention and treatment of cardiogenic thromboembolism, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolism such as brain ischemia, stroke and systemic thromboembolism and ischaemia
  • cardiac arrhythmias such as atrial fibrillation
  • the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, as well as for the prophylaxis and / or treatment of Alzheimer's disease.
  • the compounds according to the invention can inhibit tumor growth and metastasis formation, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and for the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, especially those who are undergoing major surgery or chemo- or radiotherapy.
  • the compounds according to the invention can also be used ex vivo to prevent coagulation, for example for the preservation of blood and plasma products, for the purification / pretreatment of catheters and other medical aids and devices, for coating artificial surfaces of in vivo or ex vivo medical devices and devices or biological samples containing factor Xa.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an anticoagulatory effective amount of the compound of the invention.
  • Another object of the present invention is a method for preventing blood coagulation in vitro, especially in blood or biological samples containing factor Xa, which is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.
  • compositions containing a compound of the invention and one or more other active ingredients are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • Lipid-lowering drugs in particular HMG-CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors;
  • Coronary / vasodilators especially ACE (angiotensin converting enzyme) inhibitors; AH (angiotensin U) receptor antagonists; beta-adrenoceptor antagonists; alpha 1-adrenoceptor antagonists; diuretics; Calcium channel blockers; Substances which cause an increase of cyclic guanosine monophosphate (cGMP), such as
  • Plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis enhancing compounds such as plasminogen activator inhibitor (P AI inhibitor) inhibitors or thrombin-activated fibrinolysis inhibitor (TAFI) inhibitors;
  • anticoagulant substances anticoagulants
  • platelet aggregation inhibiting substances platelet aggregation inhibitors, antiplatelet agents
  • fibrinogen receptor antagonists (glycoprotein IIb / ⁇ ia antagonists).
  • compositions containing at least one inventive compound are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the inventive compounds rapidly and / or modified donating application forms, the compounds of the invention in crystalline and / or amorphized and / or dissolved
  • Tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings containing the
  • Soft gelatin capsules Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets to be applied films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules , aqueous suspensions (lotions, shake mixtures), lipophilic Suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • the title compound is prepared by reacting 5-chlorothiophene-2-carboxylic acid with thionyl chloride, see R. Aitken et al, Arch. Pharm. (Weinheim Ger.) 1998, 331, 405-411.
  • the title compound is prepared by reacting 4-fluoronitrobenzene with morpholine-3-one [J.-M. Lehn, F. Montavon, HeIv. CMm. Ada 1976, 59, 1566-1583] and subsequent reduction of the resulting 4- (4-nitrophenyl) morpholin-3-one (see WO 01/47919, starting compounds I or ⁇ , pp. 55-57).
  • the compounds according to the invention act in particular as selective inhibitors of the blood coagulation factor Xa and do not inhibit or only at significantly higher concentrations other serine proteases such as plasmin or trypsin.
  • “Selective” refers to those coagulation factor Xa inhibitors in which the IC 50 values for factor Xa inhibition are at least 100-fold smaller than the IC 50 values for the inhibition of other serine proteases, in particular plasmin and trypsin in which, with regard to the selectivity test methods, reference is made to the test methods of Examples Bal) and Ba2) described below.
  • the enzymatic activity of human factor Xa is measured by reaction of a FXa specific chromogenic substrate.
  • the factor Xa cleaves from the chromogenic substrate p-nitroaniline. The determinations are carried out in microtiter plates as follows:
  • test substances are dissolved in different concentrations in DMSO and incubated for 10 minutes with human FXa (0.5 nmol / l dissolved in 50 mmol / l Tris buffer [QC, C-tris (hydroxymethyl) aminomethane], 150 mmol / l NaCl, 0.1% BSA [bovine serum albumin], pH 8.3 incubated) at 25 0 C.
  • human FXa 0.5 nmol / l dissolved in 50 mmol / l Tris buffer [QC, C-tris (hydroxymethyl) aminomethane], 150 mmol / l NaCl, 0.1% BSA [bovine serum albumin], pH 8.3 incubated
  • the control is pure DMSO.
  • the chromogenic substrate 150 .mu.mol / 1 Pefachrome ® FXa from Pentapharm
  • the absorbance at 405 nm is determined. The extinctions of the test mixtures with test substance are compared with the control batches without test substance and from
  • Embodiment 1 shows an IC 50 value of 5.4 nM in this test.
  • test substances are tested for their inhibition of other human serine proteases, such as trypsin and plasmin.
  • trypsin 500 mU / ml
  • plasmin 3.2 nmol / 1
  • Embodiment 1 shows in each case an IC 50 value of> 10 ⁇ M in these tests.
  • the anticoagulant effect of the test substances is determined in vitro in human and rabbit plasma.
  • blood is taken off using a 0.11 molar sodium citrate solution as a template in a sodium citrate / blood mixing ratio of 1: 9.
  • the blood is mixed well immediately after collection and centrifuged for 10 minutes at about 2500 g.
  • the supernatant is pipetted off.
  • the prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Hemoliance ® RecombiPlastin, from Instrumentation Laboratory.).
  • the test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a doubling of the prothrombin time.
  • Fasted rabbits (strain: ESD: NZW) are anesthetized by intramuscular administration of a Rompun / Ketavet solution (5 mg / kg or 40 mg / kg).
  • the thrombus formation is in an arteriovenous shunt based on that of CN.
  • Berry et al. [Semin. Thromb. Hemost. 1996, 22, 233-241].
  • the left jugular vein and the right carotid artery are dissected free.
  • An extracorporeal shunt is placed between the two vessels by means of a 10 cm long venous catheter.
  • This catheter is centered in another 4 cm long polyethylene tube (PE 160, Becton Dickenson) which incorporates a roughened and looped nylon thread to create a thrombogenic surface.
  • PE 160 polyethylene tube
  • the extracorporeal circuit is maintained for 15 minutes. Then the shunt is removed and the nylon thread with the thrombus weighed immediately. The curb weight of the Nylon thread was determined before the start of the test.
  • the test substances are administered either intravenously via an ear vein or orally by gavage prior to application of the extracorporeal circuit.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

L'invention concerne de nouvelles imino-oxazolidines, des procédés pour les produire, et leur utilisation pour le traitement et/ou la prophylaxie de maladies ainsi que pour réaliser des médicaments destinés au traitement et/ou à la prophylaxie de maladies, notamment de maladies thromboemboliques.
PCT/EP2006/003232 2005-04-22 2006-04-08 Imino-oxazolidines et leur utilisation WO2006111285A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AT06724168T ATE487714T1 (de) 2005-04-22 2006-04-08 Imino-oxazolidine und ihre verwendung als antikoagulantien
EP06724168A EP1874764B1 (fr) 2005-04-22 2006-04-08 Imino-oxazolidines et leur utilisation
DE502006008280T DE502006008280D1 (de) 2005-04-22 2006-04-08 Imino-oxazolidine und ihre verwendung als antikoagulantien
US11/919,020 US20100048548A1 (en) 2005-04-22 2006-04-08 Imino-oxazolidines and use thereof
JP2008506966A JP2008536883A (ja) 2005-04-22 2006-04-08 イミノオキサゾリジン類および抗凝固剤としてのそれらの使用
CA002605492A CA2605492A1 (fr) 2005-04-22 2006-04-08 Imino-oxazolidines et leur utilisation

Applications Claiming Priority (2)

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DE102005018690A DE102005018690A1 (de) 2005-04-22 2005-04-22 Imino-oxazolidine und ihre Verwendung
DE102005018690.4 2005-04-22

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WO2006111285A2 true WO2006111285A2 (fr) 2006-10-26
WO2006111285A3 WO2006111285A3 (fr) 2007-02-15

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DE (2) DE102005018690A1 (fr)
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DE19962924A1 (de) * 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
DE10105989A1 (de) * 2001-02-09 2002-08-14 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
DE10129725A1 (de) * 2001-06-20 2003-01-02 Bayer Ag Kombinationstherapie substituierter Oxazolidinone
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US20100048548A1 (en) 2010-02-25
CA2605492A1 (fr) 2006-10-26
WO2006111285A3 (fr) 2007-02-15
EP1874764A2 (fr) 2008-01-09
DE502006008280D1 (de) 2010-12-23
DE102005018690A1 (de) 2006-10-26
EP1874764B1 (fr) 2010-11-10
JP2008536883A (ja) 2008-09-11
ES2355154T3 (es) 2011-03-23

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